This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD) has captured the attention of the public because of its predicted prevalence in the next two decades with aging of the Boomer generation, i.e. 18% of them, or 14 million. The economic impact of a half million cases increasing to the estimated million new cases of AD per year is staggering. These figures make discovery of mechanisms and treatments for the development of the AD imperative. We have preliminary data that suggest that AD patients show pre-attentional deficits, determined using the P50 auditory evoked potential, indicative of disturbances in brainstem-thalamus processes. The results showed decreased amplitude in ~40% of subjects, indicative of decreased levels of arousal, and decreased habituation to paired stimulation, indicative of decreased sensory gating in ~60% of subjects. To date, no studies using the Psychomotor Vigilance Task (PVT), a recognized measure of attention using simple reaction time, has been used in AD patients in combination with P50 potential pre-attentional measures. The participants will be selected from our cohort of 200 well-characterized AD patients (clinical work up, history, standard battery of neuropsychological tests and an MRI). In addition to these tests, routine for assessing participants, patients will be assessed for P50 potential and PVT performance. These studies will provide data for the submission of an NIH grant application for the implementation of preclinical studies, with a view toward developing clinical trials to determine quantitatively if AD patients include two separate populations who require specific and different treatment strategies to alleviate deficits in pre-attentional and/or attentional processing. Aim 3. Determine if rTMS treatment promotes lasting improvement in tinnitus patients. All patients will be reassessed at 3 and 6 months post-rTMS on behavioral measures (RT) and questionnaires. In addition, the 5 best and 5 worst responders, based on perceived tinnitus at 6 months, will also have a repeat PET-CT at 6 months and a repeat of all assessments, including PET-CT, at 12 months. Novel Studies on Sites of Action and Mechanisms in Balance Dysfunction Specific Aim 1. Investigate the role of the ascending Reticular Activating System (RAS). We will measure the output of the RAS, i.e. pre-attentional/arousal processes, using the sleep state-dependent P50 midlatency auditory evoked potential, whose amplitude is a measure of level of arousal, and whose habituation to repetitive stimuli is a measure of sensory gating, the process behind distractibility. Specific Aim 2. Investigate thalamo-cortical processing. We will assess attentional processing using the Psychomotor Vigilance Task (PVT), a measure of simple (not choice) reaction time, and evaluate the patient's ability to sustain attention and respond in a timely manner to salient signals. We will test the participant's ability to select a specified stimulus from two or more choice stimuli presented by using the Continuous Performance Task (CPT) which is a standardized clinical measure of attention, reaction time, and distractibility. Specific Aim 3. Investigate cortical function. We will measure relative frontal lobe blood flow using Near Infrared Spectroscopy (NIRS) before and during performance of the P50 and PVT tasks to assess changes in relative blood flow to cortical regions involved in critical judgment, which are impaired in depression and other psychiatric disorders. Additionally, we will administer the Wisconsin Card Sorting Task (WCST) to access human frontal lobe function and to measure the participant's ability to shift attention from one category to another (set-shifting) with no warning using a trial and error paradigm. We will use the Operant Test Battery (OTB) to evaluate the higher cognitive functions of short-term memory, time estimation, and learning. This design will allow us to determine at which level of the neuraxis (brainstem-thalamus, thalamo-cortical, and/or cortical) patients with balance disorders manifest quantitative physiological deficits. By localizing the level of the neuraxis affected, we can develop more informed therapies that may selectively alleviate pre-attentional, attentional, and/or cognitive deficits. The proposed research will provide answers to the following questions: Do patients with balance disorders show differential changes in P50 potential amplitude, i.e. level of arousal? Do these patients show differential changes in P50 potential habituation, i.e. sensory gating? Do they show differences in mean reaction time, number of lapses, or other measures of simple attentional mechanisms? Do they show differences in higher cognitive function as evidenced by performance accuracies and latencies in short-term memory, time perception, and learning tasks? Do they show differences in relative frontal lobe blood flow before (i.e. continuous hypofrontality) and/or during (i.e. task-related) the performance of an attentional task? Quantitative physiological investigation of these potential neurological substrates for balance disorders represents a novel, comprehensive program of research with great promise for developing innovative therapies for this condition.